Mice show the way to fix genetic disorders (updated)

It's not often that words such as "rescue of neurological deficits", "therapy for cognitive impairment" and "reversal of neurological defects" are used in the titles of papers studying genetic disorders like Angelman, Down, and Rett syndromes, but a recent trio of papers does just that, offering hope for all those with complex neurodevelopmental disorders.

Angelman syndrome (AS) is sometimes called the "sister syndrome" to Prader-Willi syndrome (PWS). Delete the paternal chromosome 15 in the PWS/AS region, and you get PWS. Delete the maternal chromosome in the same area and AS results. To better study AS, a mouse model was developed in the late 90's (and unlike PWS mice, mice with AS actually live and recapitulate the characteristics of AS pretty faithfully). The symptoms associated with AS are due to disruption of the UBE3A gene on chromosome 15. The protein made by this gene regulates the stability of many other proteins, thus, exactly how disruption of UBE3A results in the AS characteristics (phenotype) has remained elusive. In studying the AS mice, however, scientists noted that a particular protein, CaMKII showed abnormally low activity. It's known that dampening of CaMKII activity can adversely affect neuronal function, so the authors of the present study [Rescue of neurological deficits in a mouse model of Angelman syndrome by reduction of alpha-CaMKII inhibitory phosphorylation. GM van Woerden et al. Nature Neurosci, 2007] reasoned that perhaps it was the decreased function of CaMKII that underlies the symptoms of AS. To prove this, they bred the AS mice to a mouse has an overactive CaMKII protein. Thus the offspring had both the defective AS gene and a compensating, overactive CaMKII protein. Happily, that combination resulted in a mouse in which almost all of the AS symptoms were alleviated. The AS/CaMKII mice had significantly less seizures, improved ability to learn (approaching that of normal mice) better memory, and improved motor coordination. Defects in long term potentiation (LTP), a process allowing neurons to change their connections and a necessary feature for efficient learning, are characteristic of AS in mice and humans, and LTP was restored to normal in AS mice with the overactive CaMKII. This paper demonstrates the importance of the CaMKII protein in mediating the effects in AS. It remains to be seen if activating CaMKII after the brain has developed or at different times during development would have the same beneficial effect, but that is a logical next step. Although not discussed in the paper, these findings also raise the possibility that drugs specifically designed to enhance CaMKII function may have a therapeutic role in AS.

A second paper uses a mouse model of Down syndrome (DS) to explore the potential of a drug therapy to improve intellectual ability. DS is caused by having three copies of chromosome 21; since chromosome 21 has many genes, it has been a difficult task to try to determine exactly which gene(s) cause the DS phenotype. The DS mouse model shows cognitive impairments similar to people with DS. It has been noted in those with DS and in the DS mouse that there is an excessive amount of GABA(A), a neurotransmitter widely expressed in the brain. GABA normally inhibits neuronal stimulation, and it may be that this excess of GABA impairs long term potentiation (LTP), a process necessary for learning. To address this, the authors of this study [Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome . F. Fernandez et al, Nature Neuroscience 2007] gave DS mice a drug that antagonizes the effects of GABA. Young adult mice given the drug for two weeks (the equivalent of approximately 2-3 years in humans) showed significantly improved learning abilities, reaching a level of learning that was similar to wild type (normal) mice. Improved LTP was noted. Interestingly, it was not necessary for the mice to be treated during the newborn period for the beneficial effect to occur, and even after a relatively short treatment period was stopped, the beneficial effects were still apparent months later. Also, since the drugs used in the study have been administered to humans before, it might be relatively easy to clinically evaluate the potential benefit of the drug in people with DS. It remains to be seen if the effect in the DS mice will be translated into humans, but this is a very encouraging study.

The final paper of this trio deals with Rett syndrome , a rare genetic syndrome that strikes girls. This disorder is particularly devastating in that girls are born healthy and begin to develop normally, but start to regress somewhere between 6-18 months and ultimately often have profound disabilities. The gene responsible for Rett syndrome is known (MECP2), but its function in development is not entirely clear. MECP2 binds to and controls the expression of many other genes throughout the genome (including some genes in the PWS region), and deficiency of MECP2 leads to abnormal neuronal development, although affected neurons don't die. In the study reported recently [Reversal of neurological defects in a mouse model of Rett syndrome . J Guy et al, Science 2007], the researchers took a mouse model of Rett syndrome, where the MECP2 gene was turned off, and reactivated the gene to see if that would have any beneficial effect. It's probably safe to say that most would have predicted that turning the gene on after development is complete would have no beneficial outcome, since, essentially, the damage would be done and would be permanent. Not so. Reactivation of the MECP2 gene in both immature and adult mice led to a reversal of even advanced neurological symptoms. A safe and efficient method to reactivate the MECP2 gene in humans remains to be developed, (and this is likely to be a difficult task) but this finding offers hope that, even for older girls with Rett syndrome, the possibility of reversing the effects of the syndrome is not unrealistic.

Altogether, these studies illustrate the power of mouse models engineered to mimic the genetic defect as human disorders. Sometimes, although not always, such mouse models provide an accurate representation of the human disease. In those cases, the models can be invaluable in understanding the disease and identifying and optimizing therapeutic interventions. Although the jump back from curing a mouse to curing a human is not always an easy one, these studies show that the time has come to be thinking about how to develop effective therapies, or even cures, for complex genetic disorders - a welcome development, indeed.


**The good news just continues. A study published in the July 2007 issue of the Proceedings of the National Academy of Sciences [Hayashi 2007] reports on mice with Fragile X syndrome , a genetic disorder of mental retardation and autism that affects boys. Mice with fragile X can be "rescued" from their symptoms if they are bred to a mouse strain that has reduced activity of a particular protein, PAK. This study not only offers hope that targeting the PAK system may ameliorate the symptoms of fragile X, it also advances our understanding of the pathways involved in brain development and autism. In a similar strategy, a group from MIT [Dolen 2007] showed that the symptoms of Fragile X syndrome can also be corrected if the fragile X mice are crossed to mice with reduced activity of a particular receptor protein, mGluR5. Overactivity of this receptor has also been proposed to underlie the symptoms of Fragile X. Again, mice deficient in both the Fragile X protein (FMRP) and mGluR5 showed correction of many of the most troubling symptoms of Fragile X syndrome, including seizures, accelerated growth, and differences in learning and memory. Both of these strategies seem to restore the balance of proteins in synapses of the neurons, allowing normal interaction of neurons to be reestablished. Because drugs targeting the mGluR5 protein are already under development, clinical trials to determine if they might be effective in treating those with Fragile X may be possible in the near future.


Topics: Research

Theresa Strong


Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.

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